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Friday, February 14, 2014

Antibiotics instead of surgery for appendicitis? No way

A retrospective study from California claims that the nonoperative management of simple appendicitis may be safe and is worth studying further.

Why am I not convinced? Because every time this subject comes up, the paper purporting to show that antibiotics are superior or even equal to surgical treatment is flawed. The trend continues with the current paper du jour which appears online in the Journal of the American College of Surgeons.

This study looked at the records of over 231,000 patients with uncomplicated appendicitis during the years 1997 to 2008. Only 3236 (1.5%) of those patients were treated non-operatively, and 10.3% of them had either a failure of antibiotic treatment or a recurrence of appendicitis during follow-up with 3% of those having perforations. Mortality rates were very low (appendectomy 0.1%, antibiotics 0.3%) and not significantly different, and hospital charges were similar in the groups matched with propensity scoring. Length of stay was significantly longer for those treated with antibiotics 3.2 days vs. 2.1 days, p < 0.001.

Sounds great, right?

I will not go into detail about the some of the important problems with this paper such as the fact that before the statistical manipulation with propensity scoring, the baseline characteristics of the patients in both groups were significantly different in all but one category. In table 1 of the paper, the number of patients available for follow-up was exactly the same as the number entering the study. That means that not a single patient was lost to follow-up, which is hard to believe since people occasionally move out of state. The reasons that patients did not undergo appendectomy could not be determined from the administrative database used.

Here are the key issues.

The paper was based on discharge diagnoses. Even with the use of CT scans for diagnosis, some cases of what seem to be simple appendicitis turn out to be more extensive at surgery. Had these patients been treated with antibiotics, the results would have been disastrous. And as a paper from the UK reported, administrative databases are notoriously unreliable for use in clinical studies.

The biggest problem with the paper touting antibiotics for appendicitis is that it includes patients over the course of the 11 years from 1997 to 2008. During that time and continuing to the present, the surgical technique of appendectomy has evolved.

If you look at the same database used by the authors (California Office of Statewide Health Planning and Development Patient Discharge), you will find that in 1999, appendectomies were done laparoscopically in 7574 of 36,740 cases or 21% of the time. Fast-forward to 2012, and note the converse—laparoscopic appendectomy was performed in 35,393 (79%) of 44,582 appendectomies.

Why is this important? The average length of stay for laparoscopic appendectomy for simple appendicitis is one day or fewer. This is less than half of the time stated in the comparison with antibiotic treatment.

In the January 2014 issue of the Journal of Trauma, a study reported 345 patients who had a laparoscopic appendectomy for uncomplicated appendicitis. Of those patients, 305 (88%) were discharged home from the post anesthesia care unit. The average time from admission to operation was five hours, and the average time spent in the PACU was just under 3 hours. The reasons that the 40 (12%) patients were admitted were lack of transportation in 19, pre-existing comorbidities in 15, and postoperative morbidity in 6. Only 4 of the patients who were discharged directly from the PACU required readmission. Thus, total complications (postop morbidity plus readmission) numbered 10 (2.8%).

Treating appendicitis with antibiotics also exposes patients to the risks of C. difficile colitis and other side effects of the drugs. The complications associated with laparoscopic appendectomy for simple appendicitis are few, and more importantly, the appendix is gone forever.

The authors concluded: "While the rate of treatment failure was 5.9% in non-operative patients, it was only 0.1% in operative patients. With concerns over controlling 30-day readmission and rising healthcare costs, these shortcomings may be substantial barriers to the consideration of non-operative approaches."

A randomized trial of antibiotics vs. surgery for uncomplicated appendicitis is underway in Finland. Judging from the wording of the abstract describing the trial, the authors are markedly biased toward the use of antibiotics. Despite this, let's hope it sheds some much needed light on this subject.

I don't understand why investigators, especially surgeons, continue to push antibiotics as an alternative to appendectomy. For simple appendicitis, laparoscopic surgery is quick, safe, and definitive.

22 comments:

Randomised trial for acute appenditis comparing antibiotics vs surgery was already published by a french team in the lancet. http://www.thelancet.com/journals/lancet/article/PIIS0140-6736%2811%2960410-8/abstract

More from the results: "In the antibiotic group, 14 (12% [7•1—18•6]) of 120 underwent an appendicectomy during the first 30 days and 30 (29% [21•4—38•9]) of 102 underwent appendicectomy between 1 month and 1 year, 26 of whom had acute appendicitis (recurrence rate 26%; 18•0—34•7)."

The authors concluded that antibiotic therapy was not inferior to appendectomy. What do you suppose they were smoking? 42% of the patients treated with antibiotics had to have an appendectomy within one year. I'm sorry, but I would call that a definitely inferior result.

I never said it was trivial. Appendectomy done laparoscopically for simple appendicitis is followed by few complications, Note the reference I included from the Journal of Trauma in my post. The recurrence rate after treating appendicitis is very high as noted in my previous comment. Suit yourself.

While I prefer less invasive strategies (antibiotics) before going in with the big guns (surgery of any type), your comment about CT scans not being able to differentiate between simple and complex leads me to not want to take the chance and go straight for the surgery. In this scenario, the laparoscopic appendectomy would be the least invasive course of action whereas cleaning up a perforated appendix would seem to me as a big job with a lot of potential complications (one being death... a complication I'd like do without).

I suspect what might be valuable in settling this once and for all is, of all things, a patient satisfaction survey. I know they have huge problems (and are negatively correlated with outcomes!). In this case, I suspect a follow-up survey with all those patients who were on anti-biotics vs. those who went to surgery would reveal just how miserable the former group was. I had a few friends who for whatever reason did not have an appendectomy- they were not happy campers for the week or more they spent in the hospital. I imagine having to come back within a year would make people even more disgruntled.

I won't say I've never done it (used antibiotics in certain cases of appendicitis, with success I might add), but to suggest it as routine is overly ambitious, to put it nicely. I've heard it compared to treatment of uncomplicated diverticulitis, which is usually not treated surgically, but these two are different animals. Plus, there is a big difference between appendectomy and sigmoid colectomy, whether open or lap.

I think the important thing to remember is that there may be a few times where we could, and maybe should, treat appendicitis with antibiotics. The trick is to know which are those few cases. If you aren't willing to recheck the patient's status frequently, you don't have ready access to surgery, or you don't have good sphincter control, go ahead and take the damn thing out already.

Probiotic experiments with the gut microbiota indicate that the appendix is a refugium of gut flora that helps replenish the microbiome after extensive intestinal dysbiosis for example from intensive antibiotic therapy for C. diff. If the appendix contains the "bad bugs" it received from the gut microbiota, the antibiotic may suppress the flora but not sterilize the whole tract so as they increase in numbers after the therapy is discontinued the same problems will reoccur. Antibiotic treatment of acute flare up followed by long term probiotic delivery perhaps in conjunction with a fecal transplant should prevent the usual reoccurrence of inflamed appendix. Will the insurance companies pay for this and will the FDA squash it, I don't know but going for surgery every time is not the way medical care advances.

Not sure if there is enough "evidence" to treat appendicitis w. ATBx but I agree, it is an interesting idea in a time of escalating c.diff. However, anecdotally, at age 10 my brother had acute appendicitis and would have died without surgery (perf). Now at age 45 he is healthy and has not been hospitalized since. He has occasionally been on antibiotics and has had no ill effects. Conversely, my neighbor, a healthy 50 year old F (with her appendix) developed c.diff after taking po clindamycin following dental work!!

Here is an excerpt from the conclusion in a 2013 article that sides with keeping the appendix intact when possible: "removal of the appendix may also impede the ability of the body to replenish helpful bacteria, and/or appendectomy might hinder helpful immune responses, such as those directed at C. difficile. Whatever the cause, appendectomy appears to be associated with an increased risk for recurrent C. difficile colitis" http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3769896/

I was treated w/ "interval" appendectomy - antibiotics for 6 weeks until laparoscopic appendectomy. I had peritonitis before and after surgery. I had six weeks of antibiotics before surgery w/ reduced activity; had to take more antibiotics after surgery; and reduced activity for six weeks post operation. I felt that I was denied appropriate care (defined as quick removal of appendix and early start on recovery) because EVERYONE else I discussed this with had their appendix removed immediately after being diagnosed with appendicitis. I tell others that if the surgeon hesitates to operate for appendicitis - put your clothes on and go to a different hospital.

DD, thanks for commenting. As you know, you can find a paper to justify anything you want to do in medicine.

Anon, it's hard to judge your case without more details. It is perfectly acceptable to treat a ruptured appendix with antibiotics if the patient is not clinically septic. Traditionally, an interval appendectomy is performed later after the inflammation has settled down. The surgery is much easier when the appendix has cooled off.

A friend of mine who is a farmer came in yesterday with very classic appy symptoms...nausea, no appetite, localized tenderness in RLQ. Since his livelihood will require him to be very busy (and active) in the next few weeks, he did not even want to hear about "possible treatment options", he said just get the thing out so I don't have to worry about it anymore. So, a laparoscope and 10 hours of bedrest later, he was back home without his markedly inflamed appendix. And just for the record, no CT scan was done.

I point this out because his income and support of his family would take a significant hit with a treatment failure from an attempt at antibiotics. I mentioned it to him during our initial discussion but we both knew it wasn't the right thing for him. Sometimes we have to consider these "intangibles" when deciding our treatment course.

Rugger, I would have preferred that, but I finished kind of late in the day, and staying over was kind of his wife's idea, not to mention they have two small children at home. I'm in a rural hospital, and it takes time to change the mindset when the same guy has been here for 40 years, and doesn't quite get what outpatient surgery is all about.

There are much larger European studies of antibiotics for appendicitis that report a far lower rate of later appendectomy than the 42% quoted in comments above - despite the fact that usual protocol in these studies is to automatically perform surgery at any recurrent symptom that might be appendicitis. Americans use mandatory appendectomy for cultural reasons: the procedure is simple and survivable enough that it could be developed before antibiotics were developed, and so was grandfathered in as the standard of care. There is no other organ whose infection is considered to automatically require chopping it out. (Would the fact that some pneumonia patients will have recurrences justify automatically removing a piece of lung at first occurrence?)

Saying "more importantly, the appendix is gone forever" accepts the false dogma that the appendix has no function and is only a source of risk whose removal is desirable. We've heard that before about other organs, e.g., the ovaries of women done with childbearing, and it's always been wrong. Dismissing evidence that bodily structures have functions with "you can find a paper to justify anything you want" denies patients the right to choose, based on the totality of the available evidence, which of two different suites of risks they would rather accept.

I take issue with your statement about much larger European studies of antibiotics for appendicitis. If you know of them, please provide me with the references and/or links.

Also, you lung analogy does quite work since we know that the lung provides an important function, unlike the appendix (so far). It may be that the appendix does have a function, but there are about 250,000 appendectomies performed every year in the US, and no one has shown an adverse effect in people who have had that operation.

I would love to be able to quote reliable figures to patients on the treatment of appendicitis with surgery vs. antibiotics. They don't exist. Can you "get away" with antibiotics for some cases of appendicitis? Yes. How do you identify those cases? I don't know.

So far, it seems, trials have been medium-sized or single-armed. The APPAC trial is planned to include 610 adults randomized to surgery or antibiotics, with telephone follow-up for ten years (!). There are several meta-analyses. Varadhan et al., BMJ 2012 344:e2156, PubMed abstract number 22491789 (free full text is available) analyzed four trials together totalling 900 patients. This analysis reports a 63% one-year "success rate" for antibiotics, mostly because 21% who were randomized to antibiotics instead received surgery, mostly because of often unspecified "clinical judgement"; of those who weren't, 20% had surgery for recurrent issues later. The relative risk reduction for complications with antibiotics vs. surgery was 31% per protocol and 39% considering only those who were actually treated with antibiotics. Another meta-analysis of RCTs involving 980 patients (Mason et al. 2012 Surg Infect (Larchmt) 13:74-84) reports a higher "failure" rate (though also an 8.5% "failure rate" for appendectomy) but a 46% reduction in complications plus reduced sick leave and pain medication usage. The 2011 Cochrane Collaboration review (CD008359, Wilms et al.) assessed five trials totalling 901 patients; of those who actually got antibiotics, 73.4% were cured without complications, including recurrence, within a year. Though the outcome was not statistically conclusive, they concluded that surgery remained the standard treatment. So someone who chooses antibiotics, where that is allowed, is avoiding upfront risks of complications and anesthesia while accepting a meaningful risk that they will have recurrent problems and ultimately have to have surgery.

As to "nobody has shown an adverse effect": Someone above quoted a paper reporting an increased risk of C.diff, which I do not automatically dismiss. The commenter above might also have quoted Clanton et al. (PubMed abstract 23983904), which reports in a chart review of 55 patients who'd had pseudomembranous colitis badly enough to have their colons cut out - I wonder if any were told about fecal transplant first? - that 44% had had appendectomies previously, significantly higher than the population average.) There is significant speculation in the literature now that the main function of the appendix is to harbor populations of essential gut flora that can recolonize the intestine after illness. This function is of particular importance to the long-term health of those who travel a lot - though one might hesitate to travel to a remote region shortly after an attack of appendicitis, given the risk of short-term recurrence. (Appendicitis rates seem to be related to diet; they're very low in Africa. Perhaps one could reduce that ca. 20% risk by lifestyle choices?)

Also, universal surgical treatment has financial implications. I saw an essay on KevinMD a while ago by a health-care worker who had chosen this option at his own employing institution - and he had to argue hard for it - because he had just a day or two before become eligible for insurance and it was not clear that he would be covered; hospitalization and surgery would have been financially devastating if he was not. I can easily see choosing to accept a 20% risk of needing more treatment later if the flip side is an 80% chance of avoiding bankruptcy. Allegedly Obamacare was supposed to fix that, but if you have a high-deductible plan, like I do, or a bronze-level high-copay plan, even covered surgeries will clean out your checking account. (My husband was conned into the last pointless cardiac ultrasound he'll ever have a couple of years ago, before we had the high-deductible plan, yet the financial repercussions of that tiny little procedure have persisted to this day - and most people would say we were middle class.)

Anon, thanks. The meta-analyses are all flawed because they include studies with mostly open appendectomies. Complication rates are much lower now that about 80% of appendectomies are done laparoscopically.

As I said, you can "get away" with antibiotic treatment as was the case with the healthcare worker. Is it good for everyone? I hope I live long enough to see the results of the Finnish randomized trial.

I thought the ACA was going to make medical care affordable for everyone. Bankruptcy should be a thing of the past.